# Biochemical mechanisms of beta cell protection through bromodomain inhibition

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $385,000

## Abstract

PROJECT SUMMARY
Autoimmune diabetes is characterized by an inflammatory reaction in and around pancreatic islets followed by
selective destruction of insulin producing β-cells. Low concordance rates of autoimmune diabetes in
monozygotic twins indicate an important but poorly understood role for epigenetic factors in diabetes initiation
and progression. Bromodomains are epigenetic “readers” of lysine acetylation on histones and transcription
factors; bromodomain binding to acetylated histones/proteins regulates transcription in a cell-type dependent
manner. Early treatment of non-obese diabetic (NOD) mice with an inhibitor of the bromodomain and
extraterminal (BET) family (Brd2-4) was recently shown to suppress development of autoimmune diabetes.
The protective effects of BET inhibition correlated with anti-inflammatory and pro-proliferative phenotypes in
macrophages and β-cells, respectively; however, the mechanisms are poorly understood. We hypothesize that
Brd4 regulates β-cell proliferation and macrophage inflammation in islets, and that inhibition of Brd2 and Brd3
are liabilities of pan-BET inhibitors in autoimmune diseases. Consistent with this hypothesis, pan-BET
inhibition is associated with impaired learning and memory as well as reduced immune system function. As
epigenetic intervention in autoimmune diabetes represents a novel therapeutic target in a primarily pediatric
population, off-target effects must be minimized. Brd4 inhibition as a therapeutic strategy in autoimmune
diabetes will be examined in three specific aims: Aim 1) Test the hypothesis that Brd4 inhibition prevents
macrophage activation and production of inflammatory mediators known to damage β-cells. Studies will build
on our preliminary data showing that pan-BET inhibitors attenuate macrophage production of inflammatory
mediators such as IL-1β and nitric oxide. Aim 2) Test the hypothesis that Brd4 inhibition protects β-cells from
cytokine-mediated damage by stimulating DNA damage repair pathways and protecting mitochondria from
damage. Studies will use insulinoma cells deficient in Brd2, Brd3, and Brd4 and chemical inhibitors to explore
the role of BET proteins in the regulation of β-cell responses to inflammatory mediators and the activation of
defense pathways that facilitate β-cell recovery from oxidative stress. Aim 3) Develop selective Brd4 inhibitors
for effective treatment of autoimmune diabetes. We provide evidence to support our innovative approach to
selectively inhibit Brd4 using covalent targeting of a specific amino acid residue unique to Brd4. Biochemical,
molecular, immunological, cell biological, genetic, and chemical biological approaches will be used to
investigate the molecular and cellular pathways through which BET inhibition protects β-cells and to develop
novel tools and reagents to selectively target the BET family of transcriptional regulators. Our long-term goals
are to elucidate the cell-type specific mechanisms of transcriptional regulation by...

## Key facts

- **NIH application ID:** 10427263
- **Project number:** 5R01DK119359-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Brian Christopher Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2018-09-20 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427263

## Citation

> US National Institutes of Health, RePORTER application 10427263, Biochemical mechanisms of beta cell protection through bromodomain inhibition (5R01DK119359-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10427263. Licensed CC0.

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